Dermonecrosis caused by spitting cobra snakebite results from toxin potentiation and is prevented by the repurposed drug varespladib

Abstract

AbstractSnakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The venom of African spitting cobras often causes permanent injury via tissue-destructive dermonecrosis at the bite site, which is ineffectively treated by current antivenoms. To address this therapeutic gap, we identified the aetiological venom toxins responsible for causing local dermonecrosis. While cytotoxic three-finger toxins were primarily responsible for causing spitting cobra cytotoxicity in cultured keratinocytes, their potentiation by phospholipases A2toxins was essential to cause dermonecrosisin vivo. This evidence of probable toxin synergism suggests that a single toxin-family inhibiting drug could prevent local envenoming. We show that local injection with the repurposed phospholipase A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a new therapeutic strategy to more effectively prevent life-changing morbidity caused by snakebite in rural Africa.Significance StatementSpitting cobra venoms cause extensive local tissue damage surrounding the site of a snakebite. This damage cannot be effectively prevented with current antivenom treatments, and patients are often left with life-changing wounds. In this study we used cellular and mouse experiments to determine which toxins in African spitting cobra venom are responsible for causing tissue damage, revealing that a combination of two different types of toxins are required to cause pathologyin vivo. We then showed that the repurposed drug, varespladib, which targets one of these toxin types, effectively prevents skin and muscle damage in mouse models of envenoming. Collectively these findings suggest that varespladib could be an effective new type of therapy for preventing snakebite morbidity in Africa.